High dosage valbenazine formulation and compositions, methods, and kits related thereto

ABSTRACT

Solid pharmaceutical compositions with high drug loading are provided. A formulation useful for the solid pharmaceutical composition includes valbenazine, or a pharmaceutically acceptable salt thereof, silicified microcrystalline cellulose, isomalt, hydroxypropyl methylcellulose, partially pregelatinized maize starch, and magnesium stearate.

BACKGROUND Technical Field

This invention related to a novel pharmaceutical composition ofL-Valine,(2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-ylester (referred to herein as “valbenazine”) and pharmaceuticallyacceptable salts, as well as to compositions, method, and kits relatingto the same.

Description of the Related Art

Dysregulation of dopaminergic systems is integral to several centralnervous system (CNS) disorders, including neurological and psychiatricdiseases and disorders. These neurological and psychiatric diseases anddisorders include hyperkinetic movement disorders, and conditions suchas schizophrenia and mood disorders. The transporter protein vesicularmonoamine transporter-2 (VMAT2) plays an important role in presynapticdopamine release and regulates monoamine uptake from the cytoplasm tothe synaptic vesicle for storage and release.

Despite the advances that have been made in this field, there remains aneed for new therapeutic products useful to treatment of neurologicaland psychiatric diseases and disorders and other related diseases orconditions described herein. One such promising agent is valbenazine.The free base form of valbenazine has the following chemical structure:

Many different factors are considered in the selection of a counter-ionfor the formation of a salt. Only the 4-toluenesulfonate salt had thecombination of properties that made it a developable form ofvalbenazine. A formulation of valbenazine:4-toluenesulfonate (1:2)(referred to herein as “valbenazine ditosylate”) has been previouslyreported in the FDA approved drug label for valbenazine ditosylate(Ingrezza®). It is manufactured in the form of size 1 hard gelatincapsule for a 40 mg unit dosage, as measured as the free base.

With an increase in dose, the high molecular weight of two4-toluenesulfonic acid counter-ions in the salt form of valbenazinecreates a unique challenge to develop a formulation with acceptablepowder flow properties. The prior art does not provide for valbenazineor valbenazine ditosylate in a form suitable for solid-dosing atpreferred high loading drug levels, particularly with regard to capsuleformation. Therapeutically acceptable capsules according to the knownformulation and procedure containing more than about 30% valbenazineditosylate were not manufacturable. Single dosage units are unavailableto patients in need of high doses of valbenazine

Many patients experience difficulty swallowing tablets and capsules.This problem can lead to a variety of adverse events and patientnoncompliance with treatment regimens. A survey of adults ondifficulties swallowing tablets and capsules suggests that this problemmay affect as many as 40 percent of Americans. (Harris Interactive Inc.for Schwarz Pharma, 2003, Pill-Swallowing Problems in America: ANational Survey of Adults. 1-39.) Individuals who find it difficult toswallow tablets and capsules frequently cite the size as the main reasonfor the difficulty in swallowing. (Fields, J. et al., Pill Propertiesthat Cause Dysphagia and Treatment Failure, Curr. Ther. Res. Clin. Exp.,2015, 77:79-82.)

Larger tablets and capsules have also been shown to affect the transitof drug products through the pharynx and esophagus. Larger tablets andcapsules have been shown to have a prolonged esophageal transit time andmay directly affect a patient's ability to swallow a particular drugproduct. This can lead to disintegration of the product in the esophagusand/or cause injury to the esophagus. The United States Food and DrugAdministration (“FDA”) has indicated “that size should be considered aspart of a single product risk/benefit profile.” (FDA Guidance forIndustry on Size, Shape, and Other Physical Attributes of GenericTablets and Capsules at 5, 1-7, June 2015.) The FDA further recommends“that the largest dimension of a tablet or capsule should not exceed 22mm and that capsules should not exceed a standard 00 size.” Id.

There remains a substantial need for improved techniques and productsfor the oral administration of valbenazine, or a pharmaceuticallyacceptable salt thereof, to patients in need thereof, including patientshaving neurological and psychiatric diseases and disorders such ashyperkinetic movement disorders, schizophrenia, and mood disorders Thepresent disclosure fulfills these and other needs, as evident inreference to the following disclosure.

BRIEF SUMMARY

The present invention generally provides a novel solid drug form ofvalbenazine or valbenazine ditosylate, as well as to compositions,methods, and/or kits for oral administration of the same.

Valbenazine has particular utility in the treatment of hyperkineticmovement disorders, including tardive dyskinesia and other conditions asdescribed in greater detail below. The solid drug form of valbenazineprovided herein provides for high loading capacity, thus allowingformulations of valbenazine in a form suitable for oral dosing. In someembodiments, the solid drug form is a solid pharmaceutical composition.In some embodiments, the solid drug form is a unit dosage form. In someembodiments, the solid drug form is a solid composition.

In one embodiment a solid pharmaceutical composition is provided ofvalbenazine, or a pharmaceutically acceptable salt thereof, silicifiedmicrocrystalline cellulose, isomalt, hydroxypropyl methylcellulose,partially pregelatinized maize starch, and magnesium stearate. In oneembodiment, the pharmaceutically acceptable salt is valbenazineditosylate.

In another embodiment, a unit dosage form of a pharmaceuticalcomposition is provided having a capsule of size 1 or smaller and atleast 80 mg of valbenazine, or a pharmaceutically acceptable saltthereof, as measured as the free base.

In another embodiment, a unit dosage form of a pharmaceuticalcomposition is provided having a capsule of size 2 or smaller and atleast 20 mg of valbenazine, or a pharmaceutically acceptable saltthereof, as measured as the free base. In one embodiment, the unitdosage form has at least 40 mg of valbenazine, or a pharmaceuticallyacceptable salt thereof, as measured as the free base.

In one embodiment, a unit dosage form of a pharmaceutical composition isprovided having a capsule of size 0 or smaller and at least 120 mg ofvalbenazine, or a pharmaceutically acceptable salt thereof, as measuredas the free base.

In another embodiment, a unit dosage form of a pharmaceuticalcomposition is provided with valbenazine ditosylate having a w/w % of atleast 35%.

In one embodiment, a unit dosage form of a pharmaceutical composition isprovided with valbenazine ditosylate having a w/w % of about 40%,silicified microcrystalline cellulose having a w/w % of about 25%,isomalt having a w/w % of about 20%, hydroxypropyl methylcellulosehaving a w/w % of about 5%, partially pregelatinized maize starch havinga w/w % of about 7.5%, and magnesium stearate having a w/w % of about2.5%.

In one embodiment is provided a method of orally administering a unitdosage form valbenazine or valbenazine ditosylate to a subject in needthereof.

In one embodiment is provided a method for treating a hyperkineticmovement disorder in a patient in need thereof by administering to thepatient a therapeutically effective amount of the solid drug form ofvalbenazine or valbenazine ditosylate.

In one embodiment is provided a method for treating a hyperkineticmovement disorder in a patient in need thereof by administering to thepatient a therapeutically effective amount of the solid pharmaceuticalcomposition of valbenazine or valbenazine ditosylate.

In one embodiment, a kit is provided with a plurality of oral unitdosage forms of a solid pharmaceutical composition of valbenazine orvalbenazine ditosylate in combination with instructions foradministration.

In one embodiment, a kit is provided with a plurality of oral unitdosage forms of a solid composition of valbenazine or valbenazineditosylate in combination with instructions for administration.

In one embodiment, a method for producing a unit dosage form ofvalbenazine ditosylate is provided.

In one embodiment, a composition is provided of valbenazine, or apharmaceutically acceptable salt thereof, silicified microcrystallinecellulose, isomalt, hydroxypropyl methylcellulose, partiallypregelatinized maize starch, and magnesium stearate.

Also provided is a solid composition of valbenazine, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient, wherein the solid composition hasa bulk density of at least about 0.5 mg/mL.

Also provided is a solid composition of valbenazine, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient, wherein the solid composition hasa tapped density of at least about 0.6 mg/mL.

Also provided is a solid composition of valbenazine, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient, wherein the solid composition hasa d(0.9) particle size distribution less than 100 μm.

Also provided is a solid composition of valbenazine, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient, wherein the solid composition hasa blend uniformity between about 90% and about 110% with a relativestandard deviation of the blend uniformity of less than about 2%.

A solid composition of valbenazine, or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable excipient,wherein the solid composition has a blend uniformity between about 90%and about 110% with a standard deviation of the blend uniformity of lessthan about 2%.

Also provided is a process for preparing a unit dosage form comprisingvalbenazine, or a pharmaceutically acceptable salt thereof, wherein theprocess comprises:

encapsulating the solid composition described herein, to produce theunit dosage form comprising valbenazine, or a pharmaceuticallyacceptable salt thereof.

Also provided is a process for preparing a unit dosage form comprisingvalbenazine, or a pharmaceutically acceptable salt thereof, wherein theprocess comprises:

encapsulating a lubricated blend to produce a solid compositioncomprising valbenazine, or a pharmaceutically acceptable salt thereof,

wherein the lubricated blend comprises granules of valbenazine, or apharmaceutically acceptable salt thereof, and at least one lubricant.

Also provided is a unit dosage form, for use in a method of treating aneurological or psychiatric disease or disorder of a patient in needthereof.

Also provided is a solid pharmaceutical composition comprising:

valbenazine, or a pharmaceutically acceptable salt thereof;

at least one water insoluble filler;

at least one water soluble diluent;

at least one binder;

at least one disintegrant; and

at least one lubricant.

Also provided is a unit dosage form of a pharmaceutical compositioncomprising:

valbenazine ditosylate having a w/w % of about 40%;

at least one water insoluble filler having a w/w % of about 25%;

at least one water soluble diluent having a w/w % of about 20%;

at least one binder having a w/w % of about 5%;

at least one disintegrant having a w/w % of about 7.5%; and

at least one lubricant having a w/w % of about 2.5%.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds, and/or compositions, and are eachhereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 shows a process flow diagram for the production of high drugloading valbenazine capsules.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment. Thus, the appearances of the phrases “in one embodiment” or“in an embodiment” in various places throughout this specification arenot necessarily all referring to the same embodiment. Furthermore, theparticular features, structures, or characteristics may be combined inany suitable manner in one or more embodiments. Also, as used in thisspecification and the appended claims, the singular forms “a,” “an,” and“the” include plural referents unless the content clearly dictatesotherwise. It should also be noted that the term “or” is generallyemployed in its sense including “and/or” unless the content clearlydictates otherwise.

As used herein, “about” means ±20% of the stated value, and includesmore specifically values of ±10%, ±5%, ±2% and ±1% of the stated value.

Hyperkinetic movement disorders represent a category of neurologicaldisorders that are characterized by unwanted and uncontrollable, orpoorly controllable, involuntary movements. The phenomenology of thesedisorders is quite variable encompassing chorea, tremor, dystonia,myoclonus, tics, other dyskinesias, jerks and shakes. Hyperkineticmovement disorders include ataxia, chorea, dystonia, hemifacial spasm,Huntington's disease, chorea associated with Huntingon's disease,myoclonus, restless leg syndrome, tardive dyskinesia, tics, Tourette'ssyndrome, and tremors.

Mood disorders represent a category of mental disorders in which theunderlying problem primarily affects a person's persistent emotionalstate (their mood). Mood disorders include: major depressive disorder(also called major depression), bipolar disorder, persistent depressivedisorder (long lasting low grade depression), cyclothymia (a mild formof bipolar disorder), catatonic depression, post-partum depression,mania, and seasonal affective disorder (SAD). Mood disorders includesubstance-induced mood disorders and mood disorders due to a medicalcondition, e.g., hypothyroidism or Parkinson's disease.

Bipolar disorder, also known as bipolar affective disorder ormanic-depressive illness, is a mental disorder characterized by periodsof elevated mood and periods of depression. The periods of elevated moodis known as mania or hypomania depending on the severity or whetherpsychosis is present. Symptoms of mania or a manic episode include along period of feeling “high” or an overly happy or outgoing mood,extreme irritability, talking very fast, racing thoughts, jumping fromone idea to another, being easily distracted, increasing activities,being overly restless, sleeping little, having an unrealistic belief inone's abilities, impulsive behavior, and engaging in pleasurable,high-risk behaviors. Symptoms of depression or a depressive episodeinclude: an overly long period of sadness or hopelessness, loss ofinterest in activities, feeling tired, problems with concentration ormemory, difficulty making decisions, being restless or irritable, changein eating or sleeping habits, and suicide ideation. Patients withbipolar disorder have a high risk of suicide and self-harm. The cause ofbipolar disorder is not completely understood, but both genetic andenvironmental factors are thought to play a role. Environmental factorsinclude long term stress and a history of child abuse.

Medications for treatment of the manic, psychotic, or depressive aspectsof bipolar disorder generally include mood stabilizers, atypicalantipsychotics, or antidepressants, in combination with psychotherapy.Sleep medications may also be used to help with sleep disturbances. Forsevere cases in which medication and psychotherapy does not work,electroconvulsive therapy may be used. Bipolar disorder usually is alifelong illness and can worsen if left untreated. Long-term, continuoustreatment is needed to control symptoms, and even with proper treatmentmood changes can still occur. Patients frequently need to try severaldifferent medications before finding ones that help control symptoms.Given the unpleasant and potentially severe side effects associated withthese medications, particularly anti-psychotic medications, a needexists to develop new therapeutics for treating mania in mood disordersand their related symptoms.

Schizophrenia affects approximately 1% of the adult population andreduces life expectancy by an average of 20 to 25 years through theimpact of the disorder on self-care and physical health, as well asthrough suicide. At the present time the etiological mechanismsunderlying schizophrenia are poorly understood. Schizophrenia isdiagnosed clinically, based on characteristic symptoms of psychosis,disorganization and so called ‘negative’ symptoms (representing areduced range of emotional expression, reduced production of speech anda lack of volition/motivation); duration of illness; impairedfunctioning; and the exclusion of other disorders such as autism andbipolar disorder. For clinicians, identifying which psychotic patientshave schizophrenia requires clinical acumen and familiarity with theDSM-IV or ICD-10 diagnostic manuals [see, e.g., Corvin, BMC Biol. 2011;9: 77].

Schizoaffective disorder is a mental health condition characterizedprimarily by symptoms of schizophrenia, such as hallucinations ordelusions, and symptoms of a mood disorder, such as mania anddepression. Diagnosis may be difficult as symptoms of schizophrenia andmood disorders are both present and many people are incorrectlydiagnosed with schizophrenia or mood disorder. Treatment forschizoaffective disorder includes medications, typically antipsychoticsand antidepressants and psychotherapy.

Antipsychotic drug therapy is a pillar in the treatment ofschizophrenia. These antipsychotic drugs, also known as neuroleptics,generally cause a reduction of the ‘positive’ symptoms of schizophrenia,namely psychosis, thought disorders, and disorganized behavior.Antipsychotics generally have a lesser influence on cognition and on the‘negative’ symptoms of the disease, which include lack of motivation andemotion, social withdrawal, lack of interest in everyday activities, andthe reduced ability to plan or carry out activities.

Obsessive-compulsive disorder (OCD) is an anxiety disorder characterizedby recurrent and persistent anxiety-provoking thoughts (obsessions) thatlead to repetitive behaviors (compulsions) that focus on alleviatingdistress caused by obsessive thoughts. Patients may or may not recognizethat the obsessions and compulsions are unreasonable, and these thoughtsand behaviors can become time-consuming and impair function.

OCD is generally treated with psychotherapy, medication or both.Cognitive behavior therapy (CBT), which teaches a person different waysof thinking, behaving, and reacting to situations that help him or herto feel less anxious or fearful without having obsessive thoughts oracting compulsively (cognitive restructuring and exposure responseprevention). However, CBT takes effort and practice to learn healthyways to cope with anxiety. Medications may also be prescribed to treatOCD. The most commonly prescribed medications are anti-anxietymedications and anti-depressants. Anti-anxiety medications begin workingright away, but should not be taken for long periods of time.Anti-depressants may take 10 to 12 weeks to start working and can causeside effects such as headache, nausea, sleep disturbance, and reducedlibido. Atypical anti-psychotics may also be prescribed. It is notunusual for OCD patients to have to try several medications beforefinding one that controls OCD symptoms.

However, even when OCD is appropriately diagnosed and treated, many OCDpatients are “treatment-resistant” or “treatment-refractory” and do notadequately respond to standard therapies. An estimated 10% to 40% of OCDpatients are treatment-refractory (Bystritsky, Mol. Psychiatry11:805-814). Treatment resistance generally refers to a lack ofsufficient improvement despite multiple adequate and appropriatetreatment trials. For mood disorders, it may be defined by failure toremit or respond clinically (50% reduction in symptoms) despite ≥2adequate antidepressant trials or failure to respond clinically despiteadequate medication trials across several neurotransmitter classes.Pallanti and Quercioli (Neuropsychopharmacol. Biol. Psychiatry30:400-412) proposed categorizing obsessive-compulsive disordertreatment response into several stages along a spectrum, ranging fromcomplete recovery (or remission) to full or partial response tonon-response (or completely refractory). Whichever definition is used,patients with treatment resistance in anxiety disorders experienceminimal restoration of function despite several appropriate treatmentexposures. Factors that contribute to treatment resistance in OCDinclude, but are not limited to, disease severity, medical comorbidity,psychiatric comorbidity, treatment non-compliance, cultural factors,childhood stressors, long-term persistent stressors, life stage, andlimitations of clinician/health system (Khalsa et al., Curr. Psychiatry,2011, 10:45-52). Invasive therapies, including some that areirreversible, such as electroconvulsive therapy, vagal nervestimulation, repetitive transcranial magnetic stimulation, and surgicalmethods, are reserved for patients with the strongest treatmentresistance. More effective treatments are therefore needed to treat thesymptoms associated with treatment refractory OCD.

Lesch-Nyhan syndrome is characterized by neurologic dysfunction,cognitive and behavioral disturbances, and uric acid overproduction andhas a prevalence of 1:380,000. Patients with this syndrome suffer fromcognitive deficits, movement disorders, and self-injurious behavior. Themost common presenting feature of Lesch-Nyhan syndrome is developmentaldelay during the first year of life; hypotonia and delayed motor skillsare usually evident by age 3-6 months. Children with Lesch-Nyhansyndrome typically fail to sit, crawl, and walk, and are ultimatelyconfined to a wheelchair. Even with effective management of symptoms,most affected individuals survive only into their second or thirddecade.

Lesch-Nyhan syndrome is inherited in an X-linked recessive pattern andis caused by deficiency of the enzyme hypoxanthine-guaninephosphoribosyltransferase (HPRT) that catalyzes the conversion ofhypoxanthine to inosine monophosphate (inosinic acid, IMP) and guanineto guanine monophosphate (guanylic acid, GMP) in the presence ofphosphoribosyl pyrophosphate. To treat hyperuricemia and thereby reducethe risk for nephrolithiasis, urate nephropathy, gouty arthritis, andtophi, overproduction of uric acid is controlled with allopurinol, whichblocks the metabolism of hypoxanthine and xanthine into uric acidcatalyzed by xanthine oxidase.

Agitation in Alzheimer's disease refers to a cluster of severalbehavioral symptoms associated with the disease. Agitation develops asthe disease progresses and occurs in addition to cognitive loss. Thecluster of symptoms includes anxiety, depression, irritability, andmotor restlessness (such as pacing, wandering, constant movement). Othersymptoms that may occur include sleep disturbances, delusions,hallucinations, compulsive behaviors, aggression, and general emotionaldistress. Agitation may occur in as many as half of all individuals withAlzheimer's disease. Agitation is associated with patients who have apoor quality of life, deteriorating family relationships andprofessional caregivers, ultimately leading to admission to aresidential care facility.

Fragile X syndrome (also called Martin-Bell syndrome) is a geneticcondition that causes a range of developmental problems includinglearning disabilities and cognitive impairment. Usually, males are moreseverely affected by this disorder than females. Fragile X syndrome isinherited in an X-linked dominant pattern. Fragile X syndrome occurs inapproximately 1 in 4,000 males and 1 in 8,000 females. This syndrome iscaused by loss of the fragile X mental retardation protein (FMRP),generally due to transcriptional silencing from a CGG repeat expansionin the 5′ untranslated region of the FMR1 gene (see, e.g., Verkerk etal., Cell 65:905-14 (1991)).

Affected individuals usually have delayed development of speech andlanguage by the age of 2 years. Most males with Fragile X syndrome havemild to moderate intellectual disability, while about one-third ofaffected females are intellectually disabled. Children with Fragile Xsyndrome may also exhibit behavioral problems, including anxiety,attentional deficits, anxiety, and hyperactive behaviors, such asfidgeting or impulsive actions. Children with Fragile X syndrome and whohave attentional deficits may be diagnosed with attention deficitdisorder (ADD), which includes an impaired ability to maintain attentionand difficulty focusing on specific tasks. About one-third ofindividuals with Fragile X syndrome have features of autism spectrumdisorders that affect communication and social interaction, for example,anxiety and repetitive, stereotyped behaviors (i.e., stereotypies).Seizures occur in about 15 percent of males and about 5 percent offemales with this syndrome.

The CGG repeat expansion in patients with Fragile X syndrome occurs morethan 200 times. When the repeat expansion occurs to a lesser degree(i.e., between about 50-200 times), an FMR1 gene permutation occurs andFMRP is produced to some degree. FMR1 gene permutation may result inanother genetic condition called Fragile X-associated tremor-ataxiasyndrome (FXTAS). FXTAS is characterized by movement difficulties andcognition problems. FXTAS is a late-onset disorder, usually occurringafter age 50; symptoms worsen with age. This condition also affectsmales more frequently and severely than females with about 1 in 3000 menaffected.

Characteristics of FXTAS include problems with coordination and balance(ataxia) and intention tremor, which is trembling or shaking of a limbwhen the affected individual is trying to perform a voluntary movement,such as reaching for an object. Most often, intention tremors developfirst, followed a few years later by ataxia. Not all persons with FXTAShave both features. Many affected individuals develop other movementproblems, such as parkinsonism, which includes tremors when not moving(resting tremor), rigidity, and unusually slow movement (bradykinesia).In addition, affected individuals may have reduced sensation, numbnessor tingling, pain, or muscle weakness in the lower limbs. Some peoplewith FXTAS experience problems with the autonomic nervous system,leading to the inability to control the bladder or bowel.

Women who have a pre-mutation in their FMR1 gene are at higher risk forprimary ovarian insufficiency (Fragile X-Associated Primary OvarianInsufficiency) and are at higher risk for having children who haveFragile X syndrome. Fragile X-Associated Primary Ovarian Insufficiencyis a cause of infertility and early menopause.

No uniformly effective intervention for managing the neurobehavioralaspects of Fragile X syndrome or FXTAS exists. More effective treatmentsare therefore needed to manage the conditions associated with thesegenetic diseases.

Autism spectrum disorder (ASD) is a range of complex neurodevelopmentdisorders, characterized by social impairments; communicationdifficulties; and restricted, repetitive, and stereotyped patterns ofbehavior (stereotypies). Autistic disorder, sometimes called autism orclassical ASD, is the most severe form of ASD. Other conditions includea milder form known as Asperger syndrome, childhood disintegrativedisorder, pervasive developmental disorder, which is not otherwisespecified (usually referred to as PDD-NOS). Although ASD variessignificantly in character and severity, it occurs in all ethnic andsocioeconomic groups and affects every age group. Based on current data,experts estimate that about one of 70 children who are age eight willhave an ASD. Males are four-five times more likely to have an ASD thanfemales. The hallmark feature of ASD is impaired social interaction.Many children with an ASD engage in repetitive movements, such asrocking and twirling, or exhibit self-abusive behavior, such as bitingor head-banging.

Depression is a common feature of mental illness, whatever its natureand origin. A person with a history of any serious psychiatric disorderhas almost as high a chance of developing major depression as someonewho has had major depression itself in the past. About 20% of the U.S.population reports at least one depressive symptom in a given month, and12% report two or more in a year. Mood disorders represent a category ofmental disorders in which the underlying problem primarily affects aperson's persistent emotional state (their mood). Bipolar disorder isless common, occurring at a rate of 1% in the general population, butsome believe the diagnosis is often overlooked because manic elation istoo rarely reported as an illness. Bipolar disorder is an illnessinvolving one or more episodes of serious mania and depression.Sometimes a person might only experience symptoms of mania. If a persononly experiences feelings of sadness, this is considered depression.During episodes of bipolar disorder, a person's mood can swing fromexcessively “high” and/or irritable to sad and hopeless, with periods ofa normal mood in between.

Major depressive disorder is one of the most common mental illnesses.Depression causes people to lose pleasure from daily life, cancomplicate other medical conditions, and can even be serious enough tolead to suicide. Depression can occur to anyone, at any age, and topeople of any race or ethnic group. Depression is usually treated withmedications, psychotherapy, or a combination of the two. Medications formajor depressive disorder fall in multiple drug classes, includingtricyclic antidepressants, monoamine oxidase inhibitors, selectiveserotonin reuptake inhibitors, and atypical antidepressants. However,most antidepressants require at least 4-6 weeks for onset ofeffectiveness, and many antidepressants have unpleasant side effects.Moreover, as many as two-thirds of patients with depression experiencetreatment failure with the first anti-depressant, and up to a third ofpatients with depression don't respond to several attempts at treatment.Given the unpleasant and potentially severe side effects associated withthese medications, a need exists to develop new therapeutics fortreating depression in mood disorders and their related symptoms.

Rett syndrome (RTT), originally termed cerebroatrophic hyperammonemia,is a rare genetic postnatal neurological disorder of the grey matter ofthe brain that affects both females and male patients, with predominanceof female ones. Rett syndrome causes problems in brain function that areresponsible for cognitive, sensory, emotional, motor, and autonomicfunction. Most frequent problems that occur include those involvinglearning, speech, sensory sensations, mood, movement, breathing, cardiacfunction, chewing, swallowing, and digestion. It is characterized bynormal early growth and development followed by a slowing ofdevelopment, loss of purposeful use of the hands, distinctive handmovements, slowed brain and head growth, problems with walking,seizures, and intellectual disability. In particular, repetitivestereotyped hand movements, such as wringing and/or repeatedly puttinghands into the mouth, are usual symptoms. Apraxia—the inability toperform motor functions—is perhaps the most severely disabling featureof Rett syndrome, interfering with every body movement, including eyegaze and speech. Children with Rett syndrome often exhibit autistic-likebehaviors in the early stages(http://www.ninds.nih.gov/disorders/rett/detail_rett.htm).

Nearly all cases of Rett syndrome are caused by a mutation in the methylCpG binding protein 2, or MECP2 gene. The MECP2 gene containsinstructions for the synthesis of a protein called methyl cytosinebinding protein 2 (MeCP2), which is needed for brain development andacts as one of the many biochemical switches that can either increasegene expression or tell other genes when to turn off and stop producingtheir own unique proteins. Because the MECP2 gene does not functionproperly in individuals with Rett syndrome, insufficient amounts orstructurally abnormal forms of the protein are produced and can causeother genes to be abnormally expressed. However, not everyone who has anMECP2 mutation has Rett syndrome. Although Rett syndrome is a geneticdisorder, less than 1 percent of recorded cases are inherited or passedfrom one generation to the next. Most cases are spontaneous, which meansthe mutation occurs randomly. Rett syndrome is estimated to affect onein every 10,000 to 15,000 live female births and in all racial andethnic groups worldwide.

Chorea-acanthocytosis (ChAc) is a neurological disorder that affectsmovements in many parts of the body. Chorea refers to the involuntaryjerking movements made by people with this disorder. People with thiscondition also have abnormal star-shaped red blood cells(acanthocytosis). This disorder is one of a group of conditions calledneuroacanthocytoses that involve neurological problems and abnormal redblood cells. Clinically is characterized by a Huntington disease-likephenotype with progressive neurological symptoms including movementdisorders, psychiatric manifestations and cognitive disturbances. Choreamay also be associated with Huntington's disease, and the methods andcompositions provided herein may be employed to treat the same.

Prevalence and incidence of chorea-acanthocytosis are not known, but itis estimated that there are around 1,000 cases worldwide. Onset is inearly adulthood and the initial presentation is often subtle cognitiveor psychiatric symptoms. During the course of the disease, most patientsdevelop a characteristic phenotype including chorea. Most patientsdevelop generalized chorea and some degree of parkinsonism. Impairmentof memory and executive functions is frequent. Psychiatricmanifestations are common and may present as schizophrenia-likepsychosis or obsessive compulsive disorder (OCD). Chorea-acanthocytosisusually progresses slowly over 15-30 years, but sudden death, presumablycaused by seizures or autonomic involvement, may occur.

Chorea-acanthocytosis is caused by various mutations in the VPS13A genecoding for chorein. No obvious genotype-phenotype correlations have beenobserved. This condition is inherited in an autosomal recessive pattern,which means both copies of the gene in each cell have mutations. Theparents of an individual with an autosomal recessive condition eachcarry one copy of the mutated gene, but they typically do not show signsand symptoms of the condition.

As used herein, “22q11.2 Deletion Syndrome (22q11.2 DS) is also known asVelocardiofacial syndrome (“VCFS”), DiGeorge syndrome, CATCH 22 and lessoften referred to as DiGeorge sequence, Microdeletion 22q11.2, Monosomy22q11, Conotruncal anomaly face syndrome, Sedlaělová syndrome,Shprintzen syndrome, Takao syndrome, or Cayler cardiofacial syndrome. Itis an autosomal dominant genetic condition that arises from the deletionof genes on chromosome 22 at band q11.2. Approximately 90% ofindividuals with VCFS have a 3 Mb deletion with the deletion of twogenes, COMT and TBX1, being specifically associated with VCFS. Only ˜10%of individuals have a smaller 1.5 Mb deletion, which also typicallyincludes the deletion of TBX1 and COMT. However, not all genes relatedto VCFS have been identified.

As used herein, “COMT” is a key enzyme for regulating catecholcompounds, including dopamine, epinephrine and norepinephrine.Individuals with VCFS have approximately 50% less COMT mRNA, COMTprotein expression, and enzyme activity compared to normal subjects. Thecharacteristic behavioral manifestations of VCFS may be related todopamine dysregulation resulting from COMT haploinsufficiency. However,that can be compounded by the presence of a low-activity COMT allele,leading to further dysregulation in patients with VCFS. COMT contains acommon functional polymorphism, Val158Met (r54680), which leads toalterations in enzyme activity. Individuals with VCFS who have a singlecopy of the Met allele have markedly low COMT activity. Compared withVCFS adults carrying the COMT Val allele, those carrying the Met alleletend to have increased risk for psychotic disorders, otherneuropsychiatric syndromes, and have more severe cognitive deficits.

Accordingly, in various embodiments as disclosed herein, methods areprovided for treating a hyperkinetic movement disorder in a subject inneed thereof by administering to the patient a therapeutically effectiveamount of the solid drug form of valbenazine or valbenazine ditosylate.In one embodiment, the hyperkinetic movement disorder is tardivedyskinesia, Tourette's syndrome, Huntington's disease, chorea associatedwith Huntington's disease, or tics. In other embodiments, thehyperkinetic movement disorder is ataxia, chorea, dystonia, hemifacialspasm, myoclonus, restless leg syndrome, or tremors.

In other embodiments, methods are provided for treating a neurologicaland/or psychiatric diseases and disorders in a subject in need thereofby administering to the patient a therapeutically effective amount ofthe solid drug form of valbenazine or valbenazine ditosylate. In oneembodiment, the neurological and/or psychiatric disease or disorder ishyperkinetic movement disorder, mood disorder, bipolar disorder,schizophrenia, schizoaffective disorder, mania in mood disorder,depression in mood disorder, treatment-refractory obsessive compulsivedisorder, neurological dysfunction associated with Lesch-Nyhan syndrome,agitation associated with Alzheimer's disease, Fragile X syndrome orFragile X-associated tremor-ataxia syndrome, autism spectrum disorder,Rett syndrome, or chorea-acanthocytosis.

As used herein, “subject” means a mammal, including a human. The term“patient” is used synonymously with “subject” within this disclosure.

As used herein, the phrase term “therapeutically effective amount”refers to an amount of a therapeutic agent to treat, ameliorate, orprevent a disease or condition, or to exhibit a detectable therapeuticor preventative effect. The effect is detected by, for example, areduction in tumor size. The effect is also detected by, for example,chemical markers, steroid levels, or antigen levels. Therapeutic effectsalso include reduction in physical symptoms, such as decreased bodytemperature. The precise effective amount for a subject will depend uponthe subject's size and health, the nature and extent of the condition,the therapeutics or combination of therapeutics selected foradministration, and other variables known to those of skill in the art.The effective amount for a given situation is determined by routineexperimentation and is within the judgment of the clinician.

As used herein, “treatment” includes therapeutic applications to slow orstop progression of a disorder, prophylactic application to preventdevelopment of a disorder, and/or reversal of a disorder. Reversal of adisorder differs from a therapeutic application which slows or stops adisorder in that with a method of reversing, not only is progression ofa disorder completely stopped, cellular behavior is moved to somedegree, toward a normal state that would be observed in the absence ofthe disorder.

As used herein, “capsule size” or “capsule size number” refers to theinternationally accepted numbering system for capsule sizes used inapproved U.S. drug products, as shown in Table 1 below.

TABLE 1 Capsule Size 000 00E 00 0E 0 1 2 3 4 5 Empty Capsule VolumeCapacity (ml) Capacity 1.37 1.00 0.90 0.78 0.68 0.48 0.36 0.27 0.20 0.13Empty Capsule Overall Closed Length (mm) 26.1 25.3 23.4 23.5 21.6 19.417.6 15.7 14.3 11.1 Tolerance (mm) ±0.3 ±0.3 ±0.3 ±0.3 ±0.3 ±0.3 ±0.3±0.3 ±0.3 ±0.4 Empty Capsule Individual Lengths (Cap) Cap (mm) 12.9512.95 11.80 11.68 10.85 9.85 8.80 8.00 7.20 6.20 Tolerance ±0.35 ±0.35±0.35 ±0.35 ±0.35 ±0.35 ±0.35 ±0.35 ±0.35 ±0.29 Empty Capsule IndividualLengths (Body) Body (mm) 22.20 22.20 20.22 20.19 18.35 16.40 15.15 13.4512.10 9.30 Tolerance ±0.35 ±0.35 ±0.35 ±0.35 ±0.35 ±0.35 ±0.35 ±0.35±0.35 ±0.29 Empty Capsule External Diameter Cap (mm) 9.91 8.58 8.56 7.657.64 6.96 6.39 5.85 5.33 4.91 Body (mm) 9.55 8.25 8.23 7.36 7.35 6.636.12 5.6 5.08 4.68

As used herein, “blend uniformity” refers to the homogeneity of a solidand can represent either one sample or the average of more than onesample.

As used herein, “content uniformity” refers to the homogeneity of thevalbenazine content among unit dosage forms, e.g. capsules, afterformulation.

As used herein, “stratified sampling” refers to a process of selectingunits deliberately from various locations within a lot or batch or fromvarious phases or periods of a process to obtain a sample. In someembodiments, stratified sampling of the blend and dosage unitsspecifically targets locations either in the blender or throughout thecompression/filling operation, which have a higher risk of producingfailing content uniformity results.

In various embodiments a solid pharmaceutical composition is provided ofvalbenazine, or a pharmaceutically acceptable salt thereof, silicifiedmicrocrystalline cellulose, isomalt, hydroxypropyl methylcellulose,partially pregelatinized maize starch, and magnesium stearate. In oneembodiment, the pharmaceutically acceptable salt is valbenazineditosylate.

In various embodiments, valbenazine, or a pharmaceutically acceptablesalt thereof, is present in the solid pharmaceutical composition at alevel ranging from about 20-160 mg as measured as the free base. In oneembodiment, valbenazine, or a pharmaceutically acceptable salt thereof,is present at a level of about 20 mg as measured as the free base. Inone embodiment, valbenazine, or a pharmaceutically acceptable saltthereof, is present at a level of about 40 mg as measured as the freebase. In one embodiment, valbenazine, or a pharmaceutically acceptablesalt thereof, is present at a level of about 60 mg as measured as thefree base. In one embodiment, valbenazine, or a pharmaceuticallyacceptable salt thereof, is present at a level of about 80 mg asmeasured as the free base. In one embodiment, valbenazine, or apharmaceutically acceptable salt thereof, is present at a level of about100 mg as measured as the free base. In one embodiment, valbenazine, ora pharmaceutically acceptable salt thereof, is present at a level ofabout 120 mg as measured as the free base. In one embodiment,valbenazine, or a pharmaceutically acceptable salt thereof, is presentat a level of about 140 mg as measured as the free base. In oneembodiment, valbenazine, or a pharmaceutically acceptable salt thereof,is present at a level of about 160 mg as measured as the free base.

In one embodiment, valbenazine ditosylate is present in a unit dosageform of a solid pharmaceutical composition at a level of at least 30% byweight of the total weight of the unit dosage form. In one embodiment,valbenazine ditosylate is present at a level of at least 35% by weightof the total weight of the unit dosage form. In one embodiment,valbenazine ditosylate is present at a level of at least 38% by weightof the total weight of the unit dosage form. In one embodiment,valbenazine ditosylate is present at a level of at least 40% by weightof the total weight of the unit dosage form. In one embodiment,valbenazine ditosylate is present at a level of at least 45% by weightof the total weight of the unit dosage form.

In one embodiment, a solid pharmaceutical composition of valbenazine, ora pharmaceutically acceptable salt thereof, is provided where the solidpharmaceutical composition is in unit dosage form suitable for oraladministration. In one embodiment, the unit dosage form is formulatedfor dosing once daily. In another embodiment, the unit dosage form isformulated for dosing twice, three times, or four times daily.

In one embodiment, a unit dosage form of a solid pharmaceuticalcomposition of valbenazine, or a pharmaceutically acceptable saltthereof, as presented herein, is provided where the unit dosage form isin capsule form. In one embodiment, the unit dosage form is an oraldosage product. In one embodiment, the capsule is size 0 or smaller. Inone embodiment, the capsule is size 1 or smaller. In one embodiment, thecapsule is size 2 or smaller. In one embodiment, the capsule is size 3or smaller.

In one embodiment, the unit dosage form capsule of the solidpharmaceutical composition of valbenazine, or a pharmaceuticallyacceptable salt thereof, as presented herein, has at least 80%dissolution at 30 minutes in a USP Paddle Dissolution Method 2 apparatusand 0.1 N HCl medium.

In another embodiment, the solid pharmaceutical composition ofvalbenazine or valbenazine ditosylate as presented herein has a bulkdensity of at least about 0.5 mg/mL. In another embodiment, the solidpharmaceutical composition of valbenazine or valbenazine ditosylate aspresented herein has a tapped density of at least about 0.6 mg/mL. Inanother embodiment, valbenazine ditosylate in the solid pharmaceuticalcomposition has a d(0.9) particle size distribution less than 100 μm.

In another embodiment, a unit dosage form of a pharmaceuticalcomposition is provided having a capsule of size 1 or smaller and atleast 80 mg of valbenazine, or a pharmaceutically acceptable saltthereof, as measured as the free base. In another embodiment, thevalbenazine 80 mg unit dosage form has a capsule of size 2 or smaller.In another embodiment, the valbenazine 80 mg unit dosage form has acapsule of size 3 or smaller.

In another embodiment, a unit dosage form of a pharmaceuticalcomposition is provided having a capsule of size 2 or smaller and atleast 20 mg of valbenazine, or a pharmaceutically acceptable saltthereof, as measured as the free base. In another embodiment, thevalbenazine 20 mg unit dosage form has a capsule of size 3 or smaller.

In another embodiment, a unit dosage form of a pharmaceuticalcomposition is provided having a capsule of size 2 or smaller and atleast 40 mg of valbenazine, or a pharmaceutically acceptable saltthereof, as measured as the free base. In another embodiment, thevalbenazine 40 mg unit dosage form has a capsule of size 3 or smaller.

In one embodiment, a unit dosage form of a pharmaceutical composition isprovided having a capsule of size 0 or smaller and at least 120 mg ofvalbenazine, or a pharmaceutically acceptable salt thereof, as measuredas the free base. In another embodiment, the valbenazine 120 mg unitdosage form has a capsule of size 1 or smaller. In another embodiment,the valbenazine 80 mg unit dosage form has a capsule of size 2 orsmaller.

In another embodiment, a unit dosage form of a pharmaceuticalcomposition is provided with valbenazine ditosylate having a w/w % of atleast 35%. In another embodiment, the valbenazine ditosylate has a w/w %of at least 38%. In another embodiment, the valbenazine ditosylate has aw/w % of at least 40%. In another embodiment, the unit dosage formfurther comprises silicified microcrystalline cellulose, isomalt,hydroxypropyl methylcellulose, partially pregelatinized maize starch,and magnesium stearate.

In one embodiment, a unit dosage form of a pharmaceutical composition isprovided with valbenazine ditosylate having a w/w % of about 40%,silicified microcrystalline cellulose having a w/w % of about 25%,isomalt having a w/w % of about 20%, hydroxypropyl methylcellulosehaving a w/w % of about 5%, partially pregelatinized maize starch havinga w/w % of about 7.5%, and magnesium stearate having a w/w % of about2.5%.

Also provided is a unit dosage form comprising a solid compositiondescribed herein.

In some embodiments, the unit dosage form has an average stratifiedcontent uniformity of between about 99% and about 100% with a standarddeviation of the mean of less than about 3.5%.

In some embodiments, the unit dosage form has an average stratifiedcontent uniformity of between about 99% and about 100% with a standarderror of the mean of less than about 3.5%.

In one embodiment is provided a method of orally administering a unitdosage form valbenazine or valbenazine ditosylate to a subject in needthereof. In some embodiments, the subject has a neurological orpsychiatric disease or disorder. In one embodiment, the subject has ahyperkinetic movement disorder. In another embodiment, the hyperkineticmovement disorder is tardive dyskinesia, Tourette's syndrome,Huntington's disease, or tics.

In some embodiments, the hyperkinetic movement disorder is tardivedyskinesia. In some embodiments, the hyperkinetic movement disorder isTourette's syndrome. In some embodiments, the hyperkinetic movementdisorder is Huntington's disease. In some embodiments, the hyperkineticmovement disorder is tics.

In some embodiments, the hyperkinetic movement disorder is choreaassociated with Huntington's disease. In some embodiments, thehyperkinetic movement disorder is ataxia, chorea, dystonia, Huntington'sdisease, myoclonus, restless leg syndrome, or tremors.

In some embodiments, the patient has been determined to have 22q11.2deletion syndrome. In some embodiments, the patient is predisposed todeveloping a psychiatric disorder due to the patient having 22q11.2deletion syndrome. In some embodiments, the patient has been determinedto have COMT haploinsufficiency. In some embodiments, the patient ispredisposed to developing a psychiatric disorder due to the patienthaving COMT haploinsufficiency.

In some embodiments, the neurological or psychiatric disease or disorderis a hyperkinetic movement disorder, mood disorder, bipolar disorder,schizophrenia, schizoaffective disorder, mania in mood disorder,depression in mood disorder, treatment-refractory obsessive compulsivedisorder, neurological dysfunction associated with Lesch-Nyhan syndrome,agitation associated with Alzheimer's disease, Fragile X syndrome orFragile X-associated tremor-ataxia syndrome, autism spectrum disorder,Rett syndrome, or chorea-acanthocytosis.

In one embodiment is provided a method for treating a hyperkineticmovement disorder in a patient in need thereof by administering to thepatient a therapeutically effective amount of the solid drug form ofvalbenazine or valbenazine ditosylate, as presented herein. In anotherembodiment, the hyperkinetic movement disorder is tardive dyskinesia,Tourette's syndrome, Huntington's disease, or tics.

Also provided is a unit dosage form, as described herein, for use in amethod of treating a neurological or psychiatric disease or disorder ofa patient in need thereof.

In the practice of the methods disclosed herein, valbenazine orpharmaceutically acceptable salt thereof may be administered to thepatient for a first period of time followed by a second period of time,wherein valbenazine or pharmaceutically acceptable salt is administeredat a lower level during the first period of time than the second periodof time. The first period of time may be, for example, days, weeks ormonths. In one embodiment, the first period of time is one week. Whenadministered daily in oral unit dosage form, valbenazine orpharmaceutically acceptable salt thereof may be present in a first unitdosage form at a level of about 40 mg as measured as the free base.Following a period of time, such as one week, a second daily oral unitdosage form may then be administered. For example, valbenazine orpharmaceutically acceptable salt thereof may be present in the secondunit dosage form at a level of about 80 mg as measured as the free base.

In one embodiment, a kit is provided with a plurality of oral unitdosage forms of a solid pharmaceutical composition of valbenazine orvalbenazine ditosylate in combination with instructions foradministration.

In one embodiment, a kit is provided with a plurality of oral unitdosage forms of a solid composition of valbenazine or valbenazineditosylate in combination with instructions for administration.

In one embodiment, a method for producing a unit dosage form ofvalbenazine ditosylate is provided according to FIG. 1.

Also provided is a process for preparing a solid composition ofvalbenazine, or a pharmaceutically acceptable salt thereof, wherein theprocess comprises:

a) subjecting a blend of valbenazine, or a pharmaceutically acceptablesalt thereof, at least one water insoluble filler, and at least onewater soluble diluent to comminution;

b) blending the product of step a) with at least one binder and at leastone disintegrant;

c) determining the blend uniformity of the product of step b); and

d) blending the product of step b) with at least one lubricant only ifthe blend uniformity satisfies a predetermined criteria to produce asolid pharmaceutical composition of valbenazine, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the process further comprises the steps of: e)determining density and/or particle size distribution of the product ofstep d); and f) subjecting the product of step d) to dry granulation toproduce granules of valbenazine, or a pharmaceutically acceptable saltthereof, only if the density and/or particle size distribution satisfiesa predetermined criteria.

In some embodiments, the process further comprises the steps of: g)determining density and/or particle size distribution of the product ofstep 0; and h) blending the granules of step f) with at least onelubricant only if the density and/or particle size distributionsatisfies a predetermined criteria.

In some embodiments, the process further comprises the steps of: i)determining density and/or blend uniformity of the product of step h);and j) encapsulating the product of step h) to produce a unit dosageform comprising valbenazine, or a pharmaceutically acceptable saltthereof, only if the density and/or blend uniformity satisfies apredetermined criteria.

In some embodiments, the process further comprises the step of:determining the disintegration and/or content uniformity of the unitdosage form.

Methods for determining disintegration, content uniformity, density,particle size distribution, and blend uniformity are known in the art,including the methods described in U.S. Pharmacopeia (“USP”) 905(Uniformity of Dosage Units (2016)); USP 711 (Dissolution (2011)); USP616 (Bulk Density and Tapped Density of Powders (2015)); USP 429 (LightDiffraction Measurement of Particle Size (2016)); and USP 701(Disintegration (2016)), each of which is incorporated herein byreference for all purposes.

Also provided is a process for preparing a unit dosage form comprisingvalbenazine, or a pharmaceutically acceptable salt thereof, wherein theprocess comprises: encapsulating solid composition as described herein,to produce the unit dosage form comprising valbenazine, or apharmaceutically acceptable salt thereof.

Also provided is a process for preparing a unit dosage form comprisingvalbenazine, or a pharmaceutically acceptable salt thereof, wherein theprocess comprises: encapsulating a lubricated blend to produce a solidcomposition comprising valbenazine, or a pharmaceutically acceptablesalt thereof, wherein the lubricated blend comprises granules ofvalbenazine, or a pharmaceutically acceptable salt thereof, and at leastone lubricant.

In some embodiments, the lubricated blend is prepared by a processcomprising the steps of: blending at least one lubricant with granulesof valbenazine, or a pharmaceutically acceptable salt thereof, toproduce a lubricated blend.

In some embodiments, the granules of valbenazine, or a pharmaceuticallyacceptable salt thereof, is prepared by a process comprising the stepsof: dry granulating a blend to produce granules of valbenazine, or apharmaceutically acceptable salt thereof. In some embodiments, drygranulating a blend comprises gravity feeding the blend through theroller compactor.

In some embodiments, the blend is prepared by a process comprising thesteps of: blending at least one lubricant with an intragranular blend toproduce the blend.

In some embodiments, the intragranular blend is prepared by a processcomprising blending a pre-blend with at least one disintegrant and atleast one binder to produce the intragranular blend.

In some embodiments, the pre-blend is prepared by a process comprisingthe steps of: blending valbenazine, or a pharmaceutically acceptablesalt thereof, with at least one water-insoluble filler and at least onewater soluble diluent to produce the pre-blend.

Also provided is a process for preparing a unit dosage form comprisingvalbenazine, or a pharmaceutically acceptable salt thereof, wherein theprocess comprises:

preparing a dispersion of valbenazine, or a pharmaceutically acceptablesalt thereof, in at least one water-insoluble filler and at least onewater soluble diluent to produce a pre-blend;

blending the pre-blend with one or more excipients to produce a blend;

granulating the blend to produce a granulated blend;

optionally blending the granulated blend with one or more excipients toproduce a lubricated blend; and

encapsulating the lubricated blend.

Also provided is a unit dosage form comprising valbenazine, or apharmaceutically acceptable salt thereof, prepared by any of theprocesses described herein.

Also provided is a solid composition of valbenazine, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient, wherein the solid composition hasa bulk density of at least about 0.5 mg/mL.

Also provided is a solid composition of valbenazine, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient, wherein the solid composition hasa tapped density of at least about 0.6 mg/mL.

Also provided is a solid composition of valbenazine, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient, wherein the solid composition hasa d(0.9) particle size distribution less than 100 μm.

Also provided is a solid composition of valbenazine, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient, wherein the solid composition hasa blend uniformity between about 90% and about 110% with a relativestandard deviation of the blend uniformity of less than about 2%. Insome embodiments, the solid composition has a blend uniformity betweenabout 95% and about 105% with a relative standard deviation of the blenduniformity of less than about 2%.

Also provided is a solid composition of valbenazine, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient, wherein the solid composition hasa blend uniformity between about 90% and about 110% with a standarddeviation of the blend uniformity of less than about 2%. In someembodiments, the solid composition has a blend uniformity between about95% and about 105% with a standard deviation of the blend uniformity ofless than about 2%.

In some embodiments, the valbenazine, or a pharmaceutically acceptablesalt thereof, is present at a level ranging from about 20-160 mg asmeasured as the free base. In some embodiments, the valbenazine, or apharmaceutically acceptable salt thereof, is present at a level of about20 mg as measured as the free base. In some embodiments, thevalbenazine, or a pharmaceutically acceptable salt thereof, is presentat a level of about 40 mg as measured as the free base. In someembodiments, the valbenazine, or a pharmaceutically acceptable saltthereof, is present at a level of about 60 mg as measured as the freebase. In some embodiments, the valbenazine, or a pharmaceuticallyacceptable salt thereof, is present at a level of about 80 mg asmeasured as the free base. In some embodiments, the valbenazine, or apharmaceutically acceptable salt thereof, is present at a level of about120 mg as measured as the free base. In some embodiments, thevalbenazine, or a pharmaceutically acceptable salt thereof, is presentat a level of about 160 mg as measured as the free base.

In some embodiments, the solid composition comprises valbenazine, or apharmaceutically acceptable salt thereof, as measured by the free base,at a level of at least about 35% w/w. In some embodiments, the solidcomposition comprises valbenazine, or a pharmaceutically acceptable saltthereof, as measured by the free base, at a level of at least about 38%w/w. In some embodiments, the solid composition comprises valbenazine,or a pharmaceutically acceptable salt thereof, as measured by the freebase, at a level of at least about 40% w/w. In some embodiments, thesolid composition comprises valbenazine, or a pharmaceuticallyacceptable salt thereof, as measured by the free base, at a level of atleast about 45% w/w. In some embodiments, the solid compositioncomprises valbenazine, or a pharmaceutically acceptable salt thereof, asmeasured by the free base, at a level of about 40% w/w.

In some embodiments, the pharmaceutically acceptable salt of valbenazineis a tosylate salt. In some embodiments, the pharmaceutically acceptablesalt of valbenazine is valbenazine ditosylate.

In some embodiments, the solid composition comprises granules of thevalbenazine, or a pharmaceutically acceptable salt thereof, and the atleast one pharmaceutically acceptable excipient. In some embodiments,the granules are prepared by dry granulation. In some embodiments, thegranules are prepared by roller compaction.

In some embodiments, the solid composition comprises a blend of thegranules of valbenazine, or a pharmaceutically acceptable salt thereof,and the at least one pharmaceutically acceptable excipient with at leastone lubricant.

In some embodiments, the at least one pharmaceutically acceptableexcipient is at least one lubricant. In some embodiments, the solidcomposition comprises at least one lubricant in an amount of betweenabout 0.25% and about 5% w/w. In some embodiments, the solid compositioncomprises at least one lubricant in an amount of about 2.5% w/w. In someembodiments, the at least one lubricant is chosen from magnesiumstearate, calcium stearate, stearic acid, talc, starch, and fumed silica(silicon dioxide). In some embodiments, the at least one lubricant ismagnesium stearate.

In some embodiments, the at least one pharmaceutically acceptableexcipient is at least one disintegrant. In some embodiments, the atleast one disintegrant is present in an amount of between about 1% andabout 10% w/w, such as between about 2% and about 9%, such as betweenabout 3% and about 8%, such as between about 4% and about 8%, such asbetween about 5% and about 8%, such as between about 6% and about 8%,such as between about 7% and about 8%. In some embodiments, the at leastone disintegrant is present in an amount of about 7.5% w/w. In someembodiments, the at least one disintegrant is chosen from starch,alginic acid, sodium starch glycolate, croscarmellose, crospovidone,cellulose, and acid-carbonate effervescent systems. In some embodiments,the at least one disintegrant is starch.

In some embodiments, the at least one pharmaceutically acceptableexcipient is at least one binder. In some embodiments, the at leastbinder is present in an amount of between about 0.5% and about 5% w/w,such as between about 2 and about 5%, such as between about 3% and about5%, such as between about 4% and about 5%. In some embodiments, the atleast binder is present in an amount of about 5% w/w. In someembodiments, the at least one binder is chosen from hypromellose,polyvinylpyrrolidone, natural gums (e.g. acacia gum), microcrystallinecellulose, methylcellulose, ethylcellulose, sucrose, starch, andgelatin. In some embodiments, the at least one binder is hypromellose.

In some embodiments, the at least one pharmaceutically acceptableexcipient is at least one water soluble diluent. In some embodiments,the at least one water soluble diluent is present in an amount ofbetween about 20% and about 95% w/w, such as between about 20% and about80%, such as between about 20% and about 60%, such as between about 20%and about 40%. In some embodiments, the at least one water solublediluent is present in an amount of about 20% w/w. In some embodiments,the at least one water soluble diluent is chosen from lactose, mannitol,isomalt, sucrose, dextrose, and sorbitol. In some embodiments, the atleast one water soluble diluent is isomalt.

In some embodiments, the at least one pharmaceutically acceptableexcipient is at least one water insoluble filler. In some embodiments,the at least one insoluble filler is present in an amount of betweenabout 20% and about 95% w/w, such as between about 20% and about 80%,such as between about 20% and about 60%, such as been about 20% andabout 40%. In some embodiments, the at least one insoluble filler ispresent in an amount of about 25% w/w. In some embodiments, the at leastone water soluble filler is chosen from microcrystalline cellulose,starch, dicalcium phosphate dihydrate, and calcium carbonate. In someembodiments, the at least one water soluble filler is microcrystallinecellulose.

In some embodiments, the solid composition is a solid pharmaceuticalcomposition.

Also provided is an oral dosage product comprising the solid compositiondescribed herein.

Also provided is a unit dosage form prepared from a solid composition ofvalbenazine, or a pharmaceutically acceptable salt thereof, and at leastone pharmaceutically acceptable excipient, wherein the solid compositionhas a bulk density of at least about 0.5 mg/mL.

Also provided is a unit dosage form prepared from a solid composition ofvalbenazine, or a pharmaceutically acceptable salt thereof, and at leastone pharmaceutically acceptable excipient, wherein the solid compositionhas a tapped density of at least about 0.6 mg/mL.

Also provided is a unit dosage form prepared from a solid composition ofvalbenazine, or a pharmaceutically acceptable salt thereof, and at leastone pharmaceutically acceptable excipient, wherein the solid compositionhas a d(0.9) particle size distribution less than 100 μm.

Also provided is a unit dosage form prepared from a solid composition ofvalbenazine, or a pharmaceutically acceptable salt thereof, and at leastone pharmaceutically acceptable excipient, wherein the solid compositionhas a blend uniformity between about 90% and about 110% with a relativestandard deviation of the blend uniformity of less than about 2%.

Also provided is a unit dosage form prepared from a solid composition ofvalbenazine, or a pharmaceutically acceptable salt thereof, and at leastone pharmaceutically acceptable excipient, wherein the solid compositionhas a blend uniformity between about 90% and about 110% with a standarddeviation of the blend uniformity of less than about 2%.

In one embodiment, a composition is provided of valbenazine, or apharmaceutically acceptable salt thereof, silicified microcrystallinecellulose, isomalt, hydroxypropyl methylcellulose, partiallypregelatinized maize starch, and magnesium stearate. In anotherembodiment, the composition has appropriate properties for unit dosagemanufacture, including de-agglomeration, granule flow, blending,uniformity, compression, encapsulation characteristics, dry granulationparameters and granule characteristics.

Physical characteristics of the granules and a final lubricated blendinclude bulk and tapped densities, flowdex, and particle sizedistribution (PSD). In one embodiment, the composition has blenduniformity for final lubricated blends, encapsulation fill weightuniformity and dissolution profiles and content uniformity. Content anduniformity of dosage units is prepared by adequate de-agglomeration andsubsequent dispersion of the drug substance in isomalt and silicifiedmicrocrystalline cellulose diluents. Improper processing parameters canresult in poor granule flow and compressibility which can impactencapsulation.

Blending is performed in a controlled environment minimizing moistureexposure. Inadequate blending can impact content and uniformity ofdosage units. Over blending with hydrophobic magnesium stearate canimpact dissolution.

Each and every process, method, composition, or use described hereinoptionally includes the limitation “wherein the oral dosage form is nota capsule comprising 80 mg valbenazine free base in combination withhypromellose, isomalt, magnesium stearate, pregelatinized starch, andsilicified microcrystalline cellulose.”

Each and every process, method, composition, or use described hereinoptionally includes the limitation “wherein the oral dosage form is nota capsule comprising 40 mg valbenazine free base in combination withcolloidal silicon dioxide, magnesium stearate, mannitol, andpregelatinized starch.”

Each and every process, method, composition, or use described hereinoptionally includes the limitation “wherein the oral dosage form is nota capsule comprising 80 mg valbenazine free base in combination withmannitol, partially pregelatinized maize starch, fumed silica, andmagnesium stearate.”

Each and every process, method, composition, or use described hereinoptionally includes the limitation “wherein the oral dosage form is nota capsule comprising 40 mg valbenazine free base in combination withmannitol, partially pregelatinized maize starch, fumed silica, andmagnesium stearate.”

EXAMPLES Example 1 Preparation of Capsule Containing 80 Mg Valbenazine

Capsules containing 80 mg valbenazine (measured as the free base) may beprepared according to the procedure set forth below, and the makeup ofexemplary tablets are listed in Table 2. A flow diagram of themanufacturing process for Valbenazine Capsules, 80 mg, which comprisesunit operations of low shear (tumble) blending, screening, rollercompaction and encapsulation, is presented in FIG. 1.

TABLE 2 Quantity 80 mg capsule (mg/ % Component capsule) (w/w) FunctionValbenazine ditosylate 145.80 40.0 Active Silicified 91.25 25.0 DiluentMicrocrystalline Cellulose Isomalt 73.00 20.0 Diluent Partiallypregelatinized 27.38 7.5 Disintegrant maize starch HydroxypropylMethylcellulose 18.25 5.0 Binder Magnesium stearate 9.12 2.5 LubricantTotal Capsule Fill Weight 364.80 100.00 — Hard gelatin capsule - Size #11 — Shell

Valbenazine ditosylate, silicified microcrystalline cellulose (USP),isomalt (United States National Formulary, “USNF”), partiallypregelatinized maize starch (USNF), hydroxypropyl methylcellulose (USNF)and magnesium stearate (USNF) were weighed according to the amounts inTable 2.

Wallpapering:

Isomalt was transferred through a screening mill equipped with an 813 μmor equivalent round-hole screen to a tote bin for blending. The screenedisomalt component was then blended.

Pre-Blending and Screening:

The following components were transferred into the tote bin through ascreening mill equipped with a ˜813 μm or equivalent round-hole screen:

a. Valbenazine ditosylate b. Silicified microcrystalline cellulose(“SMCC”) The components were then blended.

Delumping:

The blend was vacuum transferred through a buffer tank equipped with a˜813 μm or equivalent round-hole screen.

Pre-Blending #2:

The screened components were again blended.

Intragranular Blending:

The following components were then transferred, into the tote binthrough a screening mill equipped with a ˜813 μm or equivalentround-hole screen:

a. Partially pregelatinized maize starch

b. Hydroxypropyl methylcellulose

The components were then blended. Inadequate de-agglomeration andsubsequent dispersion of valbenazine ditosylate in isomalt and SMCCdiluent can potentially impact content and uniformity of dosage units.

Lubricant Blending:

Magnesium stearate was manually screened (˜1 mm sieve) (intragranularquantity adjusted as needed based on pre-lubricated blend yield—limit98%) into the opened tote bin for blending. The components were thenblended. The desired output for this step is improved flowability withincreased bulk and tapped density and improved particle sizedistribution.

Roller Compaction:

The blend was then gravity fed through a roller compactor with a millscreen of 0.8-1.0 mm. The blend characterisics are important factors toconsider for how well the blend will handle during encapsulation.Improper processing parameters can result in poor granule flow andcompressibility which impacts encapsulation. The high solubility of theAPI and excipients should not impact dissolution. All roller compactionblends showed improvement over the initial intragranular blendproperties which supports better capsule weight uniformity.

Final Lubricant Blending:

Magnesium stearate was manually screened (∫1 mm sieve) (quantity to beadjusted as needed based on pre-lubricated blend yield—limit 98%) intothe opened tote bin for blending. The components were then blended. Thedesired output for this step is a uniform and free flowing lubricatedfinal blend for encapsulation. Inadequate blending can impact contentand uniformity of dosage units. Over blending with hydrophobic magnesiumstearate can impact dissolution. Blending is performed in a controlledenvironment minimizing moisture exposure.

Encapsulation:

The lubricated blend was transferred to an automatic encapsulationmachine and encapsulated into a size 1 capsule. Improper encapsulationequipment setup can impact filled capsule shell appearance. Capsule fillweight can impact content and dose uniformity. Capsule fill plugcompression could impact dissolution and fill weight/content uniformity.

Encapsulation is performed in a controlled environment minimizingmoisture exposure.

Dedusting and metal detection of the encapsulated product was performed,and the product was weight-checked.

Example 2 Preparation of 80 Mg Valbenazine Capsule with Prior ArtFormulation

An 80 mg dose formulation strategy attempted to use the known 40 mgcapsule direct encapsulation formulation. Efforts were made to fill aSize 0 capsule with twice the amount of the 40 mg powder blend to yieldan 80 mg strength capsule, as shown in Table 3.

TABLE 3 Quantity 80 mg capsule (mg/ % Component capsule) (w/w) FunctionValbenazine ditosylate 146.0 28.21 Active Mannitol 320.0 61.82 DiluentPartially pregelatinized 40.0 7.73 Disintegrant maize starch Fumedsilica 6.4 1.24 Glidant Magnesium stearate 2.4 1.00 Lubricant TotalCapsule Fill Weight 517.6 100.00 — Hard gelatin capsule - Size #0 1 —Shell

Valbenazine ditosylate, mannitol (USP), partially pregelatinized maizestarch (USNF), fumed silica (USNF) and magnesium stearate (USNF) wereweighed according to the amounts in Table 3. A portion of the mannitol(¼) was transferred through a screening mill equipped with a ˜0.8 mm orequivalent round-hole screen to a tote bin for blending. The screenedmannitol component was then blended.

Pre-Blending and Screening:

The following components were transferred into the tote bin through ascreening mill equipped with a ˜0.8 mm or equivalent round-hole screen:

-   -   a. Valbenazine ditosylate    -   b. Fumed silica    -   c. Partially pregelatinized maize starch    -   d. Remaining mannitol (¾)—(the adjustment of mannitol weight to        compensate DS assay is performed on this fraction)        The components were blended and then transferred into        polyethylene (PE) bags. The pre-blend was transferred through a        screening mill equipped with an ˜0.8 mm or equivalent round-hole        screen to a tote bin for blending.        Final Lubricant Blending:

Magnesium stearate (quantity to be adjusted as needed based onpre-lubricated blend yield—limit 98%) was manually screened (˜1 mmsieve) into the opened tote bin for blending. The components were thenblended.

Encapsulation:

Efforts to fill a Size 0 capsule were unsuccessful. It was not possibleto compress enough powder into a compact that would fit into a Size 0capsule shell.

The various embodiments described above can be combined to providefurther embodiments. This application also claims the benefit of U.S.Provisional Patent Application No. 62/561,629, filed Sep. 21, 2017 andU.S. Provisional Patent Application No. 62/564,951, filed Sep. 28, 2017,and are incorporated herein by reference in their entirety. All of theU.S. patents, U.S. patent application publications, U.S. patentapplications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet are incorporated herein by reference, intheir entirety. Aspects of the embodiments can be modified, if necessaryto employ concepts of the various patents, applications and publicationsto provide yet further embodiments.

These and other changes can be made to the embodiments in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the claims to the specificembodiments disclosed in the specification and the claims, but should beconstrued to include all possible embodiments along with the full scopeof equivalents to which such claims are entitled. Accordingly, theclaims are not limited by the disclosure.

The invention claimed is:
 1. A solid pharmaceutical compositioncomprising: a ditosylate salt of (S)-2-amino-3-methyl-butyric acid(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylester; at least one water-insoluble filler; at least one water-solublediluent; at least one binder; at least one disintegrant; and at leastone lubricant, wherein the ditosylate salt is present in the solidpharmaceutical composition at a level of at least 30% by weight of thesolid pharmaceutical composition.
 2. The solid pharmaceuticalcomposition of claim 1, wherein the ditosylate salt is present in thesolid pharmaceutical composition at a level of at least 35% by weight ofthe solid pharmaceutical composition.
 3. The solid pharmaceuticalcomposition of claim 1, wherein the ditosylate salt is present in thesolid pharmaceutical composition at a level of at least 38% by weight ofthe solid pharmaceutical composition.
 4. The solid pharmaceuticalcomposition of claim 1, wherein the ditosylate salt is present in thesolid pharmaceutical composition at a level of at least 40% by weight ofthe solid pharmaceutical composition.
 5. The solid pharmaceuticalcomposition of claim 1, wherein said dosage form comprises: between 20%w/w and 40% w/w of the at least one water-insoluble filler; between 20%w/w and 40% w/w of the at least one water-soluble diluent; between 0.5%w/w and 5% w/w of the at least one binder; between 1% w/w and 10% w/w ofthe at least one disintegrant; and between 0.25% w/w and 5% w/w of theat least one lubricant.
 6. The solid pharmaceutical composition of claim5, wherein the at least one water-insoluble filler is microcrystallinecellulose.
 7. The solid pharmaceutical composition of claim 5, whereinthe at least one water-soluble diluent is isomalt.
 8. The solidpharmaceutical composition of claim 5, wherein the binder ishypromellose.
 9. The solid pharmaceutical composition of claim 5,wherein the at least one disintegrant is partially pregelatinized maizestarch.
 10. The solid pharmaceutical composition of claim 5, wherein theat least one lubricant is magnesium stearate.
 11. The solidpharmaceutical composition of claim 5, wherein the at least onewater-insoluble filler is microcrystalline cellulose and is present inan amount of about 25% w/w.
 12. The solid pharmaceutical composition ofclaim 5, wherein the at least one water-soluble diluent is isomalt andis present in an amount of about 20% w/w.
 13. The solid pharmaceuticalcomposition of claim 5, wherein the at least one binder is hypromelloseand is present in an amount of about 5% w/w.
 14. The solidpharmaceutical composition of claim 5, wherein the at least onedisintegrant is partially pregelatinized maize starch and is present inan amount of about 7.5% w/w.
 15. The solid pharmaceutical composition ofclaim 5, wherein the at least one lubricant is magnesium stearate and ispresent in an amount of about 2.5% w/w.
 16. The solid pharmaceuticalcomposition of claim 1, wherein the solid pharmaceutical composition issuitable for oral administration.
 17. The solid pharmaceuticalcomposition of claim 1, wherein the solid pharmaceutical composition hasa bulk density of at least about 0.5 mg/mL.
 18. The solid pharmaceuticalcomposition of claim 1, wherein the solid pharmaceutical composition hasa tapped density of at least about 0.6 mg/mL.
 19. The solidpharmaceutical composition of claim 1, wherein the solid pharmaceuticalcomposition has a blend uniformity between about 90% and about 110% witha relative standard deviation of the blend uniformity of less than about2%.
 20. The solid pharmaceutical composition of claim 1, wherein theditosylate salt has a d(0.9) particle size distribution less than 100μm.
 21. The solid pharmaceutical composition of claim 1, wherein: theditosylate salt is present in the solid pharmaceutical composition at alevel of at least 38% by weight of the solid pharmaceutical composition;the at least one water-insoluble filler is microcrystalline celluloseand is present in an amount of about 25% w/w; the at least onewater-soluble diluent is isomalt and is present in an amount of about20% w/w; the at least one binder is hypromellose and is present in anamount of about 5% w/w; the at least one disintegrant is partiallypregelatinized maize starch and is present in an amount of about 7.5%w/w; and the at least one lubricant is magnesium stearate and is presentin an amount of about 2.5% w/w.
 22. A method of treating a hyperkineticmovement disorder in a patient in need thereof, comprising orallyadministering to the patient the solid pharmaceutical composition ofclaim
 1. 23. The method according to claim 22, wherein the hyperkineticmovement disorder is tardive dyskinesia.
 24. The method according toclaim 22, wherein the hyperkinetic movement disorder is chorea.
 25. Themethod according to claim 24, wherein chorea is associated withHuntington's disease.
 26. A method of treating a hyperkinetic movementdisorder in a patient in need thereof, comprising orally administeringto the patient the solid pharmaceutical composition of claim
 21. 27. Themethod according to claim 26, wherein the hyperkinetic movement disorderis tardive dyskinesia.
 28. The method according to claim 26, wherein thehyperkinetic movement disorder is chorea.
 29. The method according toclaim 28, wherein chorea is associated with Huntington's disease. 30.The solid pharmaceutical composition of claim 1, wherein the solidpharmaceutical composition comprises granules, wherein the granulescomprise the ditosylate salt.
 31. The solid pharmaceutical compositionof claim 5, wherein the solid pharmaceutical composition comprisesgranules, wherein the granules comprise the ditosylate salt.
 32. Thesolid pharmaceutical composition of claim 21, wherein the solidpharmaceutical composition comprises granules, wherein the granulescomprise the ditosylate salt.